Asymmetric routes toward polyhydroxylated pyrrolidines: Synthesis of 1,4-dideoxy-1,4-imino-D-galactitol and 1,4-dideoxy-1,4-imino-D-glucitol

Article abstract of DOI:10.1016/j.carres.2016.09.018

Herein the total synthesis of the pyrrolidine alkaloids 1,4-dideoxy-1,4-imino-D-galactitol and its diastereoisomer 1,4-dideoxy-1,4-imino-D-glucitol is described, starting from a common optically active precursor. The key step in our approach was the doubl

Full text of DOI:10.1016/j.carres.2016.09.018

Carbohydrate Research 435 (2016) 100e105
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Asymmetric routes toward polyhydroxylated pyrrolidines: Synthesis
of 1,4-dideoxy-1,4-imino-
-glucitol
D-galactitol and 1,4-dideoxy-1,4-imino-
D
Giuliana Righi a , Emanuela Mandic' b , Carla Sappino , Ergys Dema , Paolo Bovicelli
,
*
,
**
b
b
a
a
CNR-IBPM, “Sapienza” University of Rome, Dep. Chemistry, P.le A. Moro 5, 00185, Rome, Italy
Sapienza” University of Rome, Dep. Chemistry, P.le A. Moro 5, 00185, Roma, Italy
b
“
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 August 2016
Received in revised form
Herein the total synthesis of the pyrrolidine alkaloids 1,4-dideoxy-1,4-imino-
reoisomer 1,4-dideoxy-1,4-imino-D-glucitol is described, starting from a common optically active pre-
cursor. The key step in our approach was the double diastereoselection in the asymmetric
dihydroxylation of chiral vinyl azido alcohols, obtained by means of two different regio- and stereo-
selective nucleophilic openings of the corresponding chiral vinyl epoxide.
D
-galactitol and its diaste-
30 September 2016
Accepted 30 September 2016
Available online 3 October 2016
©
2016 Elsevier Ltd. All rights reserved.
Chemical compounds:
Osmium tetraoxide (PubChem CID: 30318)
Hydroquinine 1,4-phthalazinediyl diether
(
1
(
1
PubChem CID: 45489792)
,4-dideoxy-1,4-imino-D-galactitol
PubChem CID: 10374754)
,4-dideoxy-1,4-imino-D-glucitol (PubChem
CID: 10877449)
Keywords:
Iminosugar
Polyhydroxylated pyrrolidines
1
,4-Dideoxy-1,4-imino-
D
-galactitol
-glucitol
1,4-Dideoxy-1,4-imino-
D
Asymmetric dihydroxylation
1
. Introduction
The first pyrrolidine iminosugar discovered, isolated in 1976
from Derris elliptica [2], was the (2R,5R)-bis(dihydroxymethyl)-
(3R,4R)-dihydroxypyrrolidine, DMDP [3]. Numerous similar mole-
cules (Fig. 1) subsequently were found in many different plants and
microorganisms. Although the structure of DMDP resembles that of
Polyhydroxylated pyrrolidines and piperidines, also know as
azasugars or iminosugars, are known as specific and competitive
inhibitors of glycosidases or glycosyl transferases [1]. Consequently
they may have a potential for therapeutic applications, including
treatment of diseases such as diabetes, cancer, inflammation, and
viral and bacterial infections. These effects can be exploited to
modify the glycosylation of eukaryotic cells, the metabolism of
carbohydrates and glycoconjugates, the carbohydrate-dependent
properties of glycoproteins (e.g. folding and transport) and the
carbohydrate-mediated interaction of host cells with infectious
agents.
b
-D-fructofuranose, this iminosugar shows a strong inhibition of
glycosidases I and displays antiviral activity [4].
1,4-Dideoxy-1,4-imino- -galactitol, which bears an additional
hydroxymethyl substituent, acts as a weak -glycosidase inhibitor
D
a
[5] and it has been the first known inhibitor of E. coli K12 UDP-Gal
mutase and mycobacterial galactan biosynthesis [6]. Its inhibitory
activities are highly specific and may represent a novel therapeutic
strategy for the treatment of mycobacterial infections such as
leprosy and tuberculosis.
*
Corresponding author.
Here, we report a versatile synthesis of 1,4-dideoxy-1,4-imino-
*
* Corresponding author.
E-mail address: giuliana.righi@cnr.it (G. Righi).
D-galactitol [7,8] and its diastereoisomer 1,4-dideoxy-1,4-imino-D-
http://dx.doi.org/10.1016/j.carres.2016.09.018
008-6215/© 2016 Elsevier Ltd. All rights reserved.
0

G. Righi et al. / Carbohydrate Research 435 (2016) 100e105
101
quantitative yield. The anti relationship of the azido alcohol 10 was
introduced through a regiocontrolled opening of epoxide by
bromine, using the system LiBr/Amberlyst 15 [17], to give 9 and a
subsequent substitution of the halogen by azide employing NaN
3
in
DMF (Scheme 2) [18].
To achieve better handling of the subsequent dihydroxylation
products, the hydroxyl group of 6 and 10 was protected by treating
with t-butyldimethylsilyltrifluoromethanesulfonate/2,6-lutidine to
provide the tert-butyldimethyl silyl ethers 7 and 11.
The dihydroxylation reaction, with and without chiral ligands,
was carried out on both substrates 7 and 11 (Table 2). On syn azido
alcohol 7 a 90:10 diastereomeric ratio without chiral ligand was
observed, while the presence of (DHQ) PHAL or DHQ-CLB
2
enhanced the intrinsic diastereofacial preference of the reaction
which produced 8a in almost quantitative yield. By using
2
(DHQD) PHAL or DHQD-CLB, the stereochemical outcome of the
reaction was not reversed, and the percentage of the minor product
8b was only slightly increased.
Fig. 1. Examples of naturally occurring polyhydroxylated pyrrolidines.
As shown in Table 2, similar results were obtained by per-
forming the reactions on anti azido alcohol 11: moreover, in this
glucitol [9] from the common precursor chiral epoxide 5, which
was easily obtained by the Sharpless AE of monoprotected allylic
alcohol 2 [10], starting from the commercial cis-but-2-en-1,4-diol 1
case the chiral ligand (DHQ) PHAL enabled achievement of a
2
diastereomeric ratio up to 95:5 for the intrinsically favored diol
12a.
(Scheme 1).
Reduction of the azide moiety and the subsequent ring closure
was accomplished smoothly in a one-pot reaction by treating 8a
and 12a with triphenylphosphine and then water to give lactams 13
and 15 (Scheme 3) [19]. When lactams 13 and 15 were subjected to
the boraneedimethyl sulfide reduction in refluxing THF [20], the
corresponding pyrrolidines 14 and 16 were obtained in good yield
(68% and 71%, respectively). Finally, removal of the silyl protecting
groups from the protected 14 and 16 by acid hydrolysis (HCl 37% in
The Sharpless asymmetric epoxidation was performed on the cis
allylic alcohol 2 and, despite the sluggishness of the reaction (1e2
weeks), substrate conversion was complete and epoxy alcohol 3
was obtained with a good reproducibility and excellent ee [11].
After the oxidation of 3 to aldehyde 4, followed by a Horner-
Emmons reaction [12], the corresponding a,b-unsaturated epoxy
ester 5 was obtained in good overall yield.
Recently, we reported a study on double stereodifferentiation
in the asymmetric dihydroxylation of optically active olefins [13].
As already described by other authors [14], sometimes one ligand
gives excellent results in the matched case, unlike its pseudoe-
nantiomer in the mismatched case. On the optically active vinyl
MeOH) gave 1,4-dideoxy-1,4-imino-
D-galactitol and its diastereo-
isomer 1,4-dideoxy-1,4-imino- -glucitolas hydrochlorides in
D
excellent yield, with analytical data in accordance with those pre-
viously published [7b,9c].
azido alcohols of type A (syn or anti), the use of (DHQ)
enhanced the intrinsic diastereofacial preference [15]. Instead,
DHQD) PHAL increased the production of the unnaturaldiol C,
but was not able to reverse the ratio of the diasteroisomers
Table 1).
The relevant diastereoselection obtained allowed us to prepare
attractive compounds having four contiguous stereogenic centers,
which are useful in the synthesis of a wide range of biologically
active compounds. In particular, we considered that the asym-
metric dihydroxylation on the suitable, optically active, unsatu-
rated azido alcohols 7 and 11 could represent the key step to
accessing different pyrrolidine iminosugars.
2
PHAL
2
. Conclusion
(
2
In conclusion, the total synthesis of the pyrrolidine alkaloids
1,4-dideoxy-1,4-imino-D-galactitol and 1,4-dideoxy-1,4-imino-D-
(
glucitol was achieved starting from a common precursor: the
optically active vinyl epoxide 5. The key step in our approach was
the double diastereoselection in the asymmetric dihydroxylation
of the chiral vinyl azido alcohols 7 and 11, obtained by two
different regio- and stereoselective nucleophilic opening of the
oxirane ring of 5.
Note that the use of (ꢀ)-DET in AE would allow the access to the
L-series. Moreover, if the suitable ligand able to reverse the ste-
reochemical of the AD reaction could be found, the same synthetic
sequence could lead to the 1,4-dideoxy-1,4-imino- iditol and 1,4-
The regioselective azidolysis of vinyl epoxide 5, performed using
BF3$OEt
2
and TMSN
3
[16], afforded the syn azido alcohol 6 in
ꢁ
ꢁ
Scheme 1. a) n-BuLi, TBDPSCl, THF, e50 C to rt, > 90%; b) Ti(O-i-Pr)
reflux, 75% from 3.
4
, (þ)-DET, t-BuOOH, CH
2
Cl
2
, e20 C, two weeks, 95%, ee 95%; c) TEMPO, IBDA, CH
2
Cl
2
, rt; d) LiOH, TMPA, THF,

102
G. Righi et al. / Carbohydrate Research 435 (2016) 100e105
Table 1
Dihydroxylation of vinyl azido alcohols of type A.
OH
O
OH OH
O
OH OH O
OsO
NMO
4
(5%)
R
OEt
R
OEt
R
OEt
N
3
N
3
OH
N
3
OH
A
B
C
L* = 0
L* = (DHQ) PHAL
L* = (DHQD) PHAL
90
>95
10
5
35
2
6
5
2
dideoxy-1,4-imino-altritol. Studies in this direction are currently
under investigation.
Compounds 2 [21], 3 and 4 [22] are known.
0 0 0
.2. (E, 2 S,3 R)-3-[3 -(tert-Butyl-diphenyl-silanyloxymethyl)-
oxiranyl]-acrylic acid methyl ester (5)
3
3
. Experimental section
3
.1. General methods
A suspension of 4 (1 mmol), TMPA (1.1 mmol, 0.250 g, 0.22 mL)
and LiOH (1.1 mmol, 0.027 g) in THF (10 mL) was stirred at 70 C
until consumption of the substrate (TLC monitoring). Sat. NH Cl
4
ꢁ
Organic solvents and reagents were purchased and used
without further purification unless otherwise stated. Reactions
were monitored by thin-layer chromatography (TLC) carried out on
0
soln (20 mL) was then added and the mixture was concentrated
under reduced pressure. The aqueous residue was then extracted
with EtOAc (3 ꢂ 10 mL) and the combined organic extract was
.25 mm E. Merck silica gel plates (60F-254) using UV light
(
254 nm) and visualisation was achieved by inspection under
4
washed with sat. NH Cl soln and brine until pH 7. The organic
short-wave UV light (Mineralight UVG 11 254 nm) followed by
staining with phosphomolybdic acid dip [polyphosphomolybdic
acid (5 g), ethanol (100 mL)] or ninhydrin dip [ninhydrin (5 g),
sulfuric acid (5 mL), n-butanol (100 mL)] and heating. Low tem-
perature reactions were performed in a Haake EK 101 cryostat
using an acetone bath. Unless otherwise stated, reactions were
extract was dried (Na
sure to leave the crude product, which was then purified by flash
chromatography on silica gel (hexaneeEtOAc, 9:1) to give 5 as
2
4
SO ) and concentrated under reduced pres-
yellow oil (75% from 3).
1
3
H NMR (300 MHz, CDCl ) d: 7.78e7.57 (4H, m, Ar), 7.53e7.29
(
6H, m, Ar), 6.70 (1H, dd, J ¼ 5.6, 6.5 Hz, H-3), 6.05 (1H, d,
J ¼ 15.6 Hz, H-2), 3.86e3.65 (5H, m, H-6a,bþOCH ), 3.59e3.51 (1H,
m, H-epox), 3.46e3.38 (1H, m, H-epox), 1.08 (9H, s, (CH
NMR (75 MHz, CDCl : 141.3,135.5,135.4, 134.7,133.0,132.8,129.7,
27.7, 127.6, 124.8, 61.4, 59.1, 54.7, 51.5, 26.6, 19.1. C23 Si
396.18): C 69.66, H 7.12; found C 69.70, H 7.16.
1
13
carried out under standard atmosphere. H and C NMR spectra
3
1
13
were recorded using a Varian Mercury 300 instrument ( H,
3
)
3
C).
C
3
00 MHz; 13C, 75 MHz). Residual solvent peaks were used as in-
3
) d
1
13
ternal references: chloroform ( H, d 7.26 ppm; C, d 77.00 ppm),
Chemical shifts (d) are reported in parts per million (ppm) relative
to the internal standard and coupling constant (J) in Hz. Splitting
patterns are designated as s, singlet; br s, broad singlet; d, doublet;
br d, broad doublet; dd, doublet of doublets; ddd, doublet of
doublet of doublets; t, triplet; q, quartet; m, multiplet. Unless
otherwise stated, all spectra are registered in deuterated chloro-
form. Optical rotations were measured with a Jasco Mod. DIP-370
polarimeter with a cell pathway length of 10 cm; solution con-
centrations are reported in grams per 100 ml. All chromatographic
purifications were performed using forced flow on flash silica gel
1
(
28 4
H O
Table 2
Dihydroxylation of vinyl azido alcohols 7 and 11.
(
Kiesegel 200e400 mesh from E. Merck, Germany). All procedures
are referred to 1 mmol and the yields to isolated and spectro-
scopically homogeneous compounds.
Ligand
8a/8ba,b
0:10
12a/12ba,b
90:10
9
e
DHQ-CLB
>95:5
>95:5
85:15
85:15
>95:5
>95:5
87:13
85:15
2
(DHQ) PHAL
DHQD-CLB
2
(DHQD) PHAL
a
The relative stereochemistry of the major diastereoisomer was confirmed by the
structure of the final iminosugars, by comparing the physical data with those re-
ported in literature.
b
The ratio between the two diastereomers was determined by integration of the
Scheme 2. a) TMSN
3
, BF3$OEt
2
, CH
2
Cl
2
, rt; b) TBSOTf, 2,6-lutidine, CH
2
Cl
2
, rt, 74% from
anisochronous CHOHCO
2
Et signal for each diastereoisomer in the 1H-NMR spectrum
3
5; c) LiBr, Amberlyst15, acetone, rt, >95%); d) NaN , dry DMF, rt, >95%.
of the crude mixture.

G. Righi et al. / Carbohydrate Research 435 (2016) 100e105
103
ꢁ
3 3 2
Scheme 3. a) PPh , THF, rt; b) BH -SMe , THF, rt; c) HCl (37%), MeOH, 70 C.
3.3. (E,4R,5S)-4-Azido-6-(tert-butyl-diphenyl-silanyloxy)-5-
purified by flash chromatography on silica gel (hexane/ethyl ace-
hydroxy-hex-2-enoic acid methylester (6)
tate 90:10) to give 7 as pale yellow oil (74% from 5).
1
3
H NMR (300 MHz, CDCl ) d: 7.75e7.62 (4H, m, Ar), 7.50e7.34
To a stirred solution of 5 (1 mmol) in dry CH
2
Cl
,OEt
83 mg, 0.25 mL) dropwise and the reaction mixture was left
stirring at room temperature. After complete consumption of the
substrate (TLC monitoring), the mixture was diluted with CH Cl
10 mL) and washed with aq NaHCO soln (3 mL) and brine until pH
. The organic layer was dried (Na SO ), concentrated under
2
(3 mL) were
(6H, m, Ar), 6.99 (1H, dd, J ¼ 15.8, 6.7 Hz, H-3), 6.15 (1H, dd, J ¼ 15.8,
added TMSN
3
(1 mmol, 115 mg, 0.13 mL) and BF
3
2
(2 mmol,
1.4 Hz, H-2), 4.22 (1H, ddd, J ¼ 6.7, 2.5, 1.4 Hz, H-4), 3.84e3.69 (4H,
2
m, OCH
0.81 (9H, s, (CH
(75 MHz, CDCl
127.8, 127.8, 123.4, 75.3, 64.2, 63.01, 26.8, 25.7, 19.2, 17.9, e4.8, e5.1.
Si (553.28): C 62.89, H 7.83, N 7.59; found C 62.92, H
7.87, N 7.55.
3
þH-6
a
), 3.62e3.54 (2H, m, H-5þH-6
b
),1.06 (9H, s, (CH
) C), e0.03 (3H, s, CH ), e0.16 (3H, s, CH
3 3 3 3
3
)
3
C),
). C NMR
3
) d:166.06, 143.6, 135.5, 133.02, 132.8, 129.9, 129.9,
13
2
2
(
7
3
2
4
C
29
H
43
N
3
O
4
2
reduced pressure and the crude used without chromatographic
purification.
1H NMR (300 MHz, CDCl
)
d
: 7.68e7.61 (m, 4H, Ar), 7.50e7.36
m, 6H, Ar), 6.87 (1H, dd, J ¼ 15.8, 7.03 Hz, H-3), 6.10 (1H, d,
J ¼ 15.5 Hz, H-2), 4.27 (1H, dd, J ¼ 6.05, 5.4 Hz, H-4), 3.80e3.63 (m,
3
(
3.5. (4R,5R,E)-4-Bromo-6-(tert-butyl-diphenyl-silanyloxy)-5-
hydroxy-hex-2-enoic acid methyl ester (9)
1
3
6
H, H-5þOCH
3
þH-6a,b), 2.12 (1H, br s, OH), 1.08 (9H, s, (CH
: 165.8, 141.3, 135.5, 129.9, 127.9, 124.5, 73.2,
4.04, 63.9, 51.8, 26.8, 19.2.
3 3
) C). C
NMR (75 MHz, CDCl
3
)
d
LiBr (1 mmol, 65 mg) and Amberlyst15 (1 mmol, 212 mg) were
added to 5 (1 mmol) dissolved in acetone (8 mL) and the mixture
stirred overnight at room temperature. After filtration of the
mixture, the solvent was removed in vacuum; the residue was
dissolved in EtOAc (5 mL) and washed with brine until pH 7. The
6
3
.4. (E,4R,5S)-4-Azido-5-(tert-butyl-dimethyl-silanyloxy)-6-(tert-
butyl-diphenyl-silanyloxy)-hex-2-enoic acid methyl ester (7)
2 4
organic layer was dried on Na SO , filtered and concentrated in
To a solution of 6 (1 mmol) in dry CH
2
Cl
C, were successively added 2,6-lutidine (2 mmol, 0.23 mL) and t-
BuMe SiOTf (3 mmol, 0.68 mL). The reaction mixture was stirred at
2
(6 mL) under argon at
vacuo to give 9 that was used without any purification.
ꢁ
1
0
3
H NMR (300 MHz, CDCl ) d: 7.74e7.59 (4H, m, Ar), 7.50e7.34
2
(6H, m, Ar), 7.09 (1H, dd, J ¼ 15.5,9.4 Hz, H-3), 6.15 (1H, d,
room temperature until completion (TLC monitoring) and then
diluted with 4 mL of distilled water. The aqueous phase was
J ¼ 15.5 Hz, H-2), 4.87 (1H, dd, J ¼ 9.4, 3.3 Hz, H-4), 3.82e3.67 (5H,
13
m, OCH
NMR (75 MHz, CDCl
64.6, 54.5, 51.8, 26.8, 19.1.
3
þH-6a,bþH-5), 2.58 (1H, br s, OH),1.08 (9H, s, (CH
3
)
3
C).
C
extracted twice with CH
2
Cl
2
. The combined organic layers were
3
) d: 165.9143.2, 135.5, 135.4, 128.9, 123.4, 73.0,
dried (Na SO ), filtered, and concentrated in vacuo. The crude was
2
4

104
G. Righi et al. / Carbohydrate Research 435 (2016) 100e105
3
.6. (E,4S,5S)-4-Azido-6-(tert-butyl-diphenyl-silanyloxy)-5-
dd, J ¼ 10.2,1.0 Hz, H-3), 3.99 (1H, dd, J ¼ 9.7, 2.4 Hz, H-6
dd, J ¼ 9.7, 1.2 Hz, H-6 ), 3.78 (3H, s, COOCH ), 3.55 (1H, dd, J ¼ 10.2,
.7 Hz, H-4), 3.32 (1H, br s, OH), 2.80 (1H, d, J ¼ 6.4 Hz, OH), 1.06
(9H, s, (CH C), 0.84 (9H, s, (CH C), 0.02 (3H, s, CH ), e0.13 (3H, s,
). C NMR (75 MHz, CDCl : 173.6, 135.5, 135.4, 132.1, 130.0,
a
), 3.93 (1H,
hydroxy-hex-2-enoic acid methyl ester (10)
b
3
3
To a solution of 9 (1 mmol) in dry DMF (1 mL) under argon at
3
)
3
3
)
3
3
ꢁ
13
0
C was added NaN
3
(2 mmol, 130 mg) and the mixture was left
CH
3
3
) d
stirring until complete consumption of the substrate (TLC moni-
toring). The mixture was then diluted with EtOAc (3 mL) and
127.9, 72.9, 71.2, 70.9, 65.3, 64.2, 52.7, 26.6, 25.6, 18.9, 17.9, e2.9,
e4.9, e5.1.
2 4
washed with brine. The organic layer was dried on Na SO and the
solvent removed under reduced pressure to give 10 as pale yellow
0
0
0
3.10. (1 S,3R,4S,5R)-5-[1 -(Tert-Butyl-dimethyl-silanyloxy)-2 -(tert-
butyl-diphenyl-silanyloxy)-ethyl]-3,4-dihydroxy-pyrrolidin-2-one
(13)
oil, which was used without any purification.
1
3
H NMR (300 MHz, CDCl ) d: 7.76e7.60 (4H, m, Ar), 7.52e7.27
(
1
OCH
6H, m, Ar), 6.92 (1H, dd, J ¼ 15.7, 6.8 Hz, H-3), 6.10 (1H, dd, J ¼ 15.7,
.2 Hz, H-2), 4.22 (1H, br t, J ¼ 5.8 Hz, H-4), 3.76e3.66 (6H, m,
To a solution of 8a (1 mmol) in THF (3 mL) was added triphe-
1
3
ꢁ
3
þH-6a,bþH-5), 2.68 (1H, br s, OH), 1.09 (9H, s, (CH
3
)
3
C).
C
nylphosphine (1 mmol, 223 mg) in one portion at 0 C. After stirring
ꢁ
NMR (75 MHz, CDCl
3
)
d: 165.8, 141.4, 135.4, 132.5, 130.0, 127.8,
at 0 C for 10 min, the reaction mixture was warmed to room
1
24.5, 72.9, 63.9, 63.6, 51.8, 26.8, 19.2.
temperature and stirred for 48 h. Water (20 mL) was then added.
After stirring at room temperature for an additional 12 h, the re-
action mixture was concentrated to dryness, and the residue was
purified by flash chromatography on silica gel (hexane/ethyl ace-
3.7. (E,4S,5S)-4-Azido-5-(tert-butyl-dimethyl-silanyloxy)-6-(tert-
butyl-diphenyl-silanyloxy)-hex-2-enoic acid methyl ester (11)
tate 70:30) to give 13 as colorless oil (75% from 7).
1
Following the same procedure already described for 7, after
purification by flash chromatography on silica gel (hexane/ethyl
3
H NMR (300 MHz, CDCl ) d: 7.70e7.62 (4H, m, Ar), 7.47e7.33
(6H, m, Ar), 6.1 (1H, s, NH), 5.12 (1H, br s, OH), 4.88 (1H, br s, OH),
4.36 (1H, d,J ¼ 7.6 Hz, H-2), 4.15 (1H, dd, J ¼ J ¼ 7.6 Hz, H-3), 3.78
(1H, dd, J ¼ 8.8, 4.5 Hz, H-5), 3.67 (2H, d, J ¼ 4.7 Hz, H-6a,b), 3.53 (1H,
dd, J ¼ 7.6, 4.5 Hz, H-4), 1.06 (9H, s, (CH C), 0.82 (9H, s, (CH C),
). C NMR (75 MHz, CDCl
173.5, 135.4, 131.9, 131.8, 128.4, 128.3, 76.3, 75.9, 71.0, 66.7, 59.5,
acetate 85:15) 11 was obtained as pale yellow oil (72% from 9).
1
2
1
3
H NMR (300 MHz, CDCl ) d: 7.75e7.66 (4H, m, Ar), 7.50e7.27
(
6H, m, Ar), 6.98 (1H, dd, J ¼ 15.7, 7.3 Hz, H-3), 6.13 (1H, d,
J ¼ 15.7 Hz, H-2), 4.41 (1H, dd, J ¼ 7.1, 3.3 Hz, H-4), 3.90e3.82 (1H,
m, H-5), 3.78 (3H, s, OCH ), 3.52
C), 0.86 (9H, s,
). C NMR (75 MHz,
: 165.7; 141.3; 135.5; 132.8; 132.8; 129.8; 129.7; 127.8;
27.7; 124.5; 74.6; 64.4; 51.6; 26.7; 25.6; 19.02; 17.9; e4.8; e5.1.
Si (553.28): C 62.89, H 7.83, N 7.59; found C 62.92, H
3
)
3
3 3
)
3
) d:
1
3
e0.01 (3H, s, CH
3
), e0.17 (3H, s, CH
3
3
), 3.59 (1H, dd, J ¼ 10.5, 4.5 Hz, H-6
1H, dd, J ¼ 10.5, 7.4 Hz, H-6 ), 1.08 (9H, s, (CH
CH C), 0.06 (3H, s, CH ), e0.07 (3H, s, CH
a
(
(
b
3
)
3
27.7, 25.6, 18.8, 17.7, e4.6, e5.2. C28
8.18, N 2.64; found C 63.51, H 8.20, N 2.68.
H43NO
5
Si
2
(529.27): C 63.47, H
1
3
3
)
3
3
3
3
CDCl ) d
1
0
0
0
3.11. (1 S,2R,3S,4S)-2-[1 -(tert-Butyl-dimethyl-silanyloxy)-2 -(tert-
butyl-diphenyl-silanyloxy)-ethyl]-pyrrolidine-3,4-diol (14)
C
H
29 43
N
3
O
4
2
7.82, N 7.62.
To a solution of 13 (1 mmol) in dry THF (4.34 mL) was added
ꢁ
3.8. (2R,3S,4R,5S)-4-Azido-5-(tert-butyl-dimethyl-silanyloxy)-6-
BH
3
.DMS (4 mmol, 0.15 mL) at 0 C. After stirring under nitrogen at
(
tert-butyl-diphenyl-silanyloxy)-2,3-dihydroxy-hexanoic acid
room temperature until complete consumption of the substrate
(TLC monitoring), the reaction was quenched by cautiously adding
methanol until gas evolution ceased. Additional methanol was
added and the solvents were evaporated. The residue was dissolved
in methanol and 2 N HCl was added to the solution. The mixture
was refluxed for 10 min and after cooling, the solution was evap-
methyl ester (8a)
To a solution of 7 (1 mmol) in 9 mL of acetone/water (8:1) were
added NMO (2 mmol, 270 mg), (DHQ)
and OsO (0.05 mmol, 0.63 mL of a 2,5% tert-butanol solution) and
the mixture left stirring overnight at room temperature. The reac-
tion was then quenched with Na (2.5 mmol, 395 mg); the
2
PHAL (0.15 mmol, 0.117 g)
4
orated and the pH was adjusted to 11e12 with a 15% sol of NH
4
OH.
2 2 3
S O
The solution was evaporated and the residue purified by flash
mixture left stirring for 1 h and then transferred in a separative
funnel. The aqueous layer was extracted with EtOAc, the combined
3 3
chromatography on silica gel (eluent: CHCl /CH OH 98:2) to afford
14 as colorless oil (68%).
1
organic layers dried over Na
2
SO
4
and the solvent removed under
3
H NMR (300 MHZ, CDCl ) d: 7.83e7.51 (4H, m, Ar), 7.51e7.32
reduced pressure to give 8a as colorless oil, which was used
(6H, m, Ar), 4.39e3.95 (2H, m, H-2þH-3), 3.95e3.51 (3H, m, H-
a,bþH-5), 3.32e2.98 (3H,m, H-1a,bþNHþH-4), 2.27 (2H, br s,
2xOH), 1.06 (9H, s, (CH C), 0.76 (9H, s, (CH C), e0.15 (3H, s, CH ),
). C NMR (75 MHZ, CDCl : 135.7, 135.5, 132.3,
132.1, 131.9, 129.9, 128.8, 128.6, 127.8, 127.8, 80.8, 75.8, 73.5, 70.2,
65.4, 60.7, 26.8, 25.8, 19.2, 17.9, e2.8, e5.1. C28 Si (515.29): C
without any purification.
6
1
H NMR (300 MHz, CDCl
3
)
d: 7.75e7.62 (4H, m, Ar), 7.50e7.32
3
)
3
3
)
3
3
13
(
5
4
1
6H, m, Ar), 4.52 (1H, d, J ¼ 1.2 Hz, H-2), 4.20e4.07 (2H, m, H-3þH-
e0.18 (3H,s, CH
3
3
) d
), 3.83 (3H, s, OCH
.6 Hz, H-6
), 3.60 (1H, dd, J ¼ 3.6,1.1 Hz, H-4), 2.46 (2H, br s, 2xOH),
C), 0.83 (9H, s, (CH C), e0.05(3H, s, CH ), e0.17
). C NMR (75 MHz, CDCl : 173.8, 135.5, 134.8, 129.9,
3
), 3.88e3.73 (1H, m, H-6
a
), 3.68 (1H, dd, J ¼ 9.5,
b
H
45NO
4
2
.06 (9H, s, (CH
3
)
3
3
)
3
3
65.20, H 8.79, N 2.72; found C 65.23, H 8.83, N 2.76.
13
(
3H, s, CH
3
3
) d
127.8, 72.1, 70.8, 70.3, 64.1, 61.9, 52.9, 26.8, 25.6, 19.1, 17.9, e4.8,
3.12. 1,4-Dideoxy-1,4-imino-D-galactitol
e5.3.
To 14 (1 mmol) in MeOH (1 mL) was added HCl (37%, 1 mL) and
ꢁ
3.9. (2R,3S,4S,5S)-4-Azido-5-(tert-butyl-dimethyl-silanyloxy)-6-
the resultant mixture was stirred at 70 C until complete con-
(
tert-butyl-diphenyl-silanyloxy)-2,3-dihydroxy-hexanoic acid
sumption of the substrate (TLC monitoring). After cooling to room
temperature, the mixture was diluted with EtOH (0.5 mL) and
methyl ester (12a)
CH
3
CN (5 mL) followed by removal of the solvents. The residual oil
-MeOH 1:1) to give
Following the same procedure already described for 8a, 12a was
was purified by flash chromatography (CHCl
3
obtained as colorless oil and used without any purification.
the known 1,4-dideoxy-1,4-imino-D-galactitol·HCl salt) as white
1
ꢁ
1
H NMR (300 MHz, CDCl
3
)
d: 7.73e7.65 (4H, m, Ar), 7.55e7.27
crystals (92%). mp ¼ 100e102 C.
a
D
2
¼ ꢀ22 (c ¼ 1.5, H O). H NMR
(
6H, m, Ar), 4.5 (1H, d, J ¼ 1.01 Hz, H-2), 4.28 (1H, m, H-5), 4.10 (1H,
(400 MHz, D
2
O)
d: 4.27e4.19 (1H, br t, J ¼ 2.8 Hz, H-2), 4.06 (1H, br t,

G. Righi et al. / Carbohydrate Research 435 (2016) 100e105
105
J ¼ 3.5 Hz, H-3), 3.98e3.82 (1H, m, H-5), 3.68 (1H, dd, J ¼ 12.1,
5.5 Hz,H-4), 3.60 (1H, dd, J ¼ 12.4, 4.5 Hz, H-1
a
d
), 3.40 (1H, dd,
0
13
3
.7 Hz, H-6), 3.56 (1H, dd, J ¼ 12.2, 4.9 Hz, H-6 ), 3.52e3.37 (2H, m,
J ¼ 12.4,2.7 Hz, H-1
b
). C NMR (400 MHz, CDCl
3
)
: 75.3, 74.8, 68.7,
0
13
þ
H-4þH-1), 3.23 (1H, dd, J ¼ 2.6, 12.4 Hz, H-1 ). C NMR (100 MHz,
66.4, 62.9, 50.4. HR-MS (ES Q-TOF) Calcd for C
164.0971 Found: 164.0415.
6
H
14NO
4
(MþH ):
D
2
O)
d
: 76.2, 74.2, 68.7, 66.4, 62.9, 49.6. HR-MS (ES Q-TOF) Calcd for
þ
C
6
H14NO
4
(MþH ): 164.0971 Found: 164.0484.
0
0
0
Acknowledgements
3
.13. (1 S,3R,4S,5S)-5-[1 -(tert-Butyl-dimethyl-silanyloxy)-2 -(tert-
butyl-diphenyl-silanyloxy)-ethyl]-3,4-dihydroxy-pyrrolidin-2-one
15)
Funding: This work was supported by MIUR (Ministry of Uni-
versity and Research ePRIN 2010e2011) and Flagship Project
NanoMAX.
(
Following the same procedure already described for 13, after
purification by flash chromatography on silica gel (hexane/ethyl
acetate 85:15) 15 was obtained as colorless oil (77%).
References
1
3
H NMR (300 MHz, CDCl ) d:7.73e7.65 (4H,m), 7.55e7.27(6H,m),
6
4
.20 (1H,d, J ¼ 4.1 Hz,NH), 4.67 (1H, br s, OH), 4.45 (1H, br s, OH),
.39 (1H, dd, J ¼ 7.3 Hz, H-3), 4.33 (1H, d, J ¼ 7.3 Hz, H-2), 3.82
¼ J
¼ 7.7 Hz J
), 3.62e3.58 (2H, m, H-6
[1] (a) P. Compain, O.R. Martin, Iminosugars: from Synthesis to Therapeutic Ap-
plications, Wiley, Chichester, 2007;
1
2
(
(
b) B.G. Winchester, Tetrahedron Asymm. 20 (2009) 645e651;
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(
1H, ddd, J
1
2
¼ J
3
¼ 4.1 Hz, H-5), 3.73 (1H, dd, J ¼ 10.1,
7
0
.8 Hz, H-6
.84 (9H, s, (CH
a
b
þH-4), 1.06 (9H, s, (CH
3
)
3
C),
hedron Lett. 50 (2009) 6906e6908.
13
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)
3
C), 0.07 (3H, s, CH
3
), e0.05 (3H, s, CH
3
). C NMR
(1976) 747e749.
(
75 MHz, CDCl
3
)
d:173.7, 135.4,132.6, 131.9, 131.8, 131.6, 129.7, 128.4,
[
[
[
3] (a) T.M. Wrodnigg, MonatsheftefürChemie 133 (2002) 393e426;
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128.3, 127.7, 127.6, 76.4, 75.8, 72.3, 65.7, 59.9, 26.7, 25.7, 18.9, 17.7,
e4.8, e5.1. C28
H43NO
5
Si
2
(529.27): C 63.47, H 8.18, N 2.64; found C
1
953e1955.
5] I. Lundt, R. Madsen, S.A. Daher, B. Winchester, Tetrahedron 50 (1994)
513e7520.
6
3.50, H 8.23, N 2.65.
7
0
0
0
[6] R.E. Lee, M.D. Smith, R.J. Nash, R.C. Griffiths, M. McNeil, R.K. Grewal, W. Yan,
G.S. Besra, P.J. Brennan, G.W.J. Fleet, Tetrahedron Lett. 38 (1997) 6733e6736.
3.14. (1 S,2S,3S,4S)-2-[1 -(tert-Butyl-dimethyl-silanyloxy)-2 -(tert-
butyl-diphenyl-silanyloxy)-ethyl]-pyrrolidine-3,4-diol (16)
[
[
[
7] (a) C.R. Bernotas, Tetrahedron Lett. 31 (1990) 469e472;
b) I. Lundt, R. Madsen, Synthesis (1993) 720e724;
(c) H. Paulsen, K. Steinert, K. Heyns, Chem. Ber. 103 (1970) 1599e1620;
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8] (a) D.-P. Pham-Huu, Y. Gizaw, J.N. BeMiller, L. Petru ꢀs , Tetrahedron Lett. 43
2002) 383e385;
(b) D.-P. Pham-Huu, Y. Gizaw, J.N. BeMiller, L. Petru ꢀs , Tetrahedron (2003)
413e9417.
9] (a) D.D. Long, R.J.E. Stetz, R.J. Nash, D.G. Marquess, J.D. Lloyd, A.L. Winters,
N. Asano, G.W.J. Fleet, J. Chem. Soc. Perkin Trans. 1 (1999) 901e908;
(b) J.G. Buchanan, K.W. Lumbard, R.J. Sturgeon, D.K. Thompson,
R.H. Wightman, J. Chem. Soc. Perkin Trans. 1 (1990) 699e706;
(
Following the same procedure already described for 14, after
purification by flash chromatography on silica gel (hexane/ethyl
acetate 85:15) 16 was obtained as colorless oil (71%).
(
(
1
3
H NMR (300 MHZ, CDCl ) d:7.74e7.59 (4H, m), 7.59e7.36
9
(
3
4
6H,m), 4.45e4.29 (2H, m, H-5þH-2),4.24 (1H, d, J ¼ 4.4 Hz, H-3),
.91(1H, br s, OH), 3.72e3.62 (2H, m, H-6a,b), 3.25e3.07 (3H, m, H-
þH-1a,b), 2.28 (1H, br s, OH), 1.62 (1H, br s, NH), 1.04 (9H, s,
(
CH
3
)
3
C), 0.76 (9H, s, (CH
C NMR (75 MHZ, CDCl
28.6, 128.4, 127.9, 127.8, 77.2, 75.6, 74.3, 67.8, 65.2, 60.2, 26.8, 25.6,
9.1, 17.8, e4.6, e5.1. C28 Si (515.29): C 65.20, H 8.79, N 2.72;
found C 65.24, H 8.83, N 2.75.
3 3 3 3
) C), 0.01 (3H,s, CH ), e0.18 (3H, s, CH ).
1
3
(c) G.W.J. Fleet, J.C. Son, Tetrahedron 44 (1988) 2637e2647.
10] L. Xiaojiin, D. Lantrip, P.L. Fuchs, J. Am. Chem. Soc. 125 (2003) 14262e14263.
[11] J.M. Escudier, M. Baltas, L. Gorrichon, Tetrahedron 49 (1993) 5253e5266.
3
) d:135.6, 135.5, 132.1, 132.0, 132.04, 131.9,
[
1
1
[
12] F. Bonadies, A. Cardi, A. Lattanzi, L.R. Orelli, A. Scettri, Tetrahedron Lett. 35
1994) 3383e3386.
13] G. Righi, P. Bovicelli, I. Tirotta, C. Sappino, E. Mandic', Chirality 28 (2016)
87e393.
[14] K. Morikawar, K.B. Sharpless, Tetrahedron Lett. 34 (1993) 5575e5578.
H45NO
4
2
(
[
3
3.15. 1,4-Dideoxy-1,4-imino-D-glucitol
[
[
[
[
15] G. Righi, P. Bovicelli, E. Mandic', G.C.M. Naponiello, I. Tirotta, Tetrahedron 68
(2012) 2984e2992.
Following the same procedure already described for 1,4-
dideoxy-1,4-imino-D-galactitol, after purification by flash chro-
matography on silica gel (CHCl -MeOH 1:1) 1,4-dideoxy-1,4-imino-
D-galactitol·HCl salt) was obtained as white crystals (90%).
mp ¼ 138e140 C.
16] G. Righi, L. Salvati Manni, P. Bovicelli, R. Pelagalli, Tetrahedron Lett. 52 (2011)
3895e3896.
17] G. Righi, P. Bovicelli, R. Antonioletti, E. Fazzolari, Tetrahedron Lett. 41 (2000)
3
9315e9318.
18] G. Righi, S. Ciambrone, C. D'Achille, A. Leonelli, C. Bonini, Tetrahedron 62
(2006) 11821e11826.
[19] H. Sun, K.A. Abboud, N.A. Horenstein, Tetrahedron 61 (2005) 10462e10469.
20] R. Fu, Y. Du, Z.-Y. Li, W.-X. Xu, P.Q. Huang, Tetrahedron 65 (2009) 9765e9771.
21] J.M. Chong, S. Wang, J. Org. Chem. 52 (1987) 2596e2598.
[22] J.M. Escudier, M. Baltas, L. Gorrichon, Tetrahedron 49 (1993) 5253e5266.
ꢁ
ꢁ
a
D
¼ ꢀ26 (c ¼ 2, H
2
O).
1
H NMR (400 MHz, CDCl
3
)
d
:4.41e4.34 (2H, m, H-3þH-2), 4.09
[
[
(
1H, ddd,,J
1
¼ J
2
¼ J
3
¼ 5.5 Hz, H-5), 3.79 (1H, dd, J ¼ 11.9,5.3 Hz, H-
6
a
), 3.75 (1H,dd,J ¼ 11.9, 5.7 Hz, H-6
b
), 3.63 (1H, dd, J ¼ 10.1,